Etiology: Finding the Cause
Identifying and understanding the factors that lead to breast cancer in individual women and in the population as a whole is crucial. Through this work, we can learn how to prevent breast cancer, for example, by discovering causative factors that can then be eliminated or reduced, or by identifying conditions that predispose a person to breast cancer and for which there may be preventive treatments.
Conclusions
Environment and gene/environment interactions: nature and nurture
One cause of breast cancer may be traced to how the body handles carcinogens once it is exposed to them. Certain recognized environmental carcinogens are not able to cause cancer until after enzymes within the body have changed them into their toxic forms. Other enzymes in the body are able to convert these carcinogens to safe forms. Regina Goth-Goldstein, Ph.D., at the Lawrence Berkeley National Laboratory, completed an IDEA project to examine the degree to which the ability to activate or detoxify certain carcinogens influences the risk of developing breast cancer. She investigated the genes that regulate the toxicity of a category of carcinogens, called polycyclic aromatic hydrocarbons (PAH) that cause breast cancer in animals . She found that the levels of the products from the activating gene, CYP1A1, were generally higher in the normal breast tissue from breast cancer patients than in healthy individuals. She also found that breast cancer patients tend to be missing the detoxifying gene, GSTM1, more often than further individuals without the disease. These observations are not statistically significant, indicating that further study is necessary; however, they do point out possible avenues where the relationship between genetics and carcinogens can be explored.
At one level, known risk factors for breast cancer can be understood as measures of the cumulative exposure of the breast to estrogen and, perhaps, progesterone—hormones that cause breast cells to grow and divide. Exposure to estrogen and progesterone is thought to be influenced both by genetic differences and environmental exposures. Thus, understanding the role of each of these influences, and how they interact, is essential. Heather S. Feigelson, Ph.D., M.P.H., at the University of Southern California, and colleagues are working within a model they developed for breast cancer that includes genes involved in the metabolism of estrogen in the body, such as those that transport estrogen to the breast and those that convert estrogen from less active to more active forms. Dr. Feigelson's current research is based on work in her lab that showed that women who have a particular form of a gene called CYP17 are at a 2.5 fold increased risk of developing advanced breast cancer. Further investigation, with CBCRP support, found that the CYP17 genotype was associated with estrogen and progesterone levels among 83 college-age women. Estrogen measurements during the menstrual cycle showed significantly higher levels among those women with the A2 form of CYP17; progesterone was also significantly higher in these women. These data provide the first direct evidence of genetic control of serum hormone levels. Continuing this research, Dr. Feigelson found suggestive evidence that among cancer-free women, those with the A2 form of CYPI7 are less likely than women with the A1 form to report current estrogen replacement therapy use and are less likely to be long term users of estrogen replacement therapy. This may be because CYP17 A2 women do not have as many menopausal symptoms compared to A1 women because of their higher endogenous hormone levels. These data may have important implications for women trying to weigh the risks and benefits of estrogen replacement therapy.
Hormones and nutrition: understanding the modern woman's lifestyle
Stephen Howell, M.D., at the University of California, San Diego, completed a 2-year Research Project to study the Molecular Control of Breast Exposure to Selenium. A novel gene and protein, termed hASNA, is part of a molecular “pump” that determines the concentration of such metal ions as selenium inside cells. It is believed that selenium exerts a protective effect to neutralize the environmental toxic effects of cadmium, arsenite, and nickel on cells. Dr. Howell reported that certain breast tumor samples contained elevated levels of hASNA, and that induction of hASNA production in MCF10-A cells will cause a hypersensitivity to arsenite. The normal breast does not appear to express hASNA. In additional work, it was shown that hASNA interacts with metallothionein-II as detected using a yeast 2-hybrid screen, and a monoclonal antibody was developed to detect and measure the amounts of this protein. The association of certain genes to potential environmental factors opens the door to future work on the genetic epidemiology of this research topic.
Research in Progress
Environment and gene/environment interactions: nature and nurture
Viruses have been shown to cause breast cancer in mice. Is it possible that exposure to a virus found in cows (BLV) could produce a similar effect in humans? In order to do this humans must be exposed to the virus and it must be able to get inside of cells. Gertrude Buehring, Ph.D. and her postdoctoral fellow Linda Kingsbury, Ph.D., at the University of California, Berkeley, are exploring whether these two criteria are fulfilled. Dr. Buehring is investigating whether humans are actually exposed to the virus and finds that 93% of 200 volunteers appear to be. The next step is to determine whether people are exposed to live virus or inactive virus from sources such as cooked meats. Dr. Kingsbury has determined the best approach for uncovering cell receptors (gateways into the cell) for BLV and is now trying to determine whether human cells have receptors for BLV.
Sue Ann Ingles, Ph.D., at the University of Southern California, is looking into the genetic basis for the hypothesis that vitamin D may prevent cancer by interacting with vitamin D receptors in the breast and other tissues. The vitamin D receptor plays a key role in this process and occurs in at least two different genetic “types.” Her goal is to develop genetic “markers” that can be used to measure vitamin D receptor types, and to determine whether women with specific vitamin D receptor types are relatively protected against breast cancer. Although the study is not yet complete, findings to date suggest that among Latinas, one specific vitamin D receptor type confers protection against breast cancer. Women who have inherited the protective type of vitamin D receptor gene from both parents appear to have approximately one-third the risk of developing breast cancer compared to women who inherited two of the “non-protective” vitamin D receptor genes. Women who have inherited one protective and one nonprotective vitamin D receptor gene are at intermediate risk. Unfortunately, these genetic markers do not work well for the African-American population; therefore, during the second year of the grant, they plan to combine several vitamin D receptor genetic markers to develop a test for the protectivetype vitamin D receptor gene in the African-American population.
Hormones and nutrition: understanding the modern woman's lifestyle
James Felton, Ph.D., at the Lawrence Livermore National Laboratory, is investigating the properties of PhIP, a suspected breast carcinogen found in some cooked meats. PhIP needs to be metabolized before it becomes dangerous. Dr. Felton found that individuals metabolize PhIP into different types and proportions of breakdown products. He is currently analyzing these products and developing an animal model that generates the same breakdown products. Ultimately, he will determine which breakdown products are most closely associated with developing breast cancer.
Other searches for the causes
Thomas Balon, Ph.D., of the City of Hope National Medical Center, is looking at the relationship between breast cancer and nitric oxide, a molecule that regulates cells' ability to produce energy from sugars. So far, he found that when an enzyme that produces nitric oxide is inhibited, it results in decreased sugar transport only in estrogen-dependent breast cancer cells. Regulation of nitric oxide may have a differential effect on how estrogen-dependent cells convert sugars to energy, thereby affecting how they grow and multiply.
There are a number of other very interesting ongoing CBCRP studies into the etiology of breast cancer that were funded in the last two years, but which require extensive subject recruitment, data gathering, complex laboratory and statistical analysis before any results can be obtained. Therefore, there are as yet no findings of note for such promising ongoing projects as the work of Karla Kerlikowske, M.D., at the San Francisco VA Medical Center, looking at predictors of recurrent breast tumors in women with ductal carcinoma in situ; the work of Thomas Mack, M.D., M.P.H., at the University of Southern California, looking at whether mammographic density (a predictor of risk in White women) is an inherited characteristic, and, if so, whether adult exposures can modify this density; the work of Anna Wu, Ph.D., at the University of Southern California, investigating whether individual differences among women in processing (because of polymorphisms or differences in our genetic make-up) certain commonly encountered environmental compounds found in cooked meats, tobacco smoke, etc. are likely to be influencing the risk for breast cancer; the work of Gerhard Coetzee, Ph.D., at the University of Southern California, Norris Cancer Center, attempting to explain how variants of the CYP17 actually cause differences in the activity of the enzymes they regulate, and, in turn, how they might be related to the risk of developing breast cancer; and, the work of Peggy Reynolds, Ph.D., at The Public Health Institute looking at organochlorine pesticides, which were widely used in the past in industrial processes, and dioxins (a byproduct in the manufacture of petroleumbased herbicides), and whether there may be association between exposure to these compounds and the risk of breast cancer in African American women. Findings from these studies over the next few years should provide more clues to the perplexing problem of the causes of breast cancer.
Recently Initiated Research
In 1998, the CBCRP awarded six grants that explore the causes of breast cancer in different ways. One of these is a Training Program Award (Ronald Ross, M.D., at the University of Southern California), designed to train graduate students in a multidisciplinary environment that will encourage innovative thinking about breast cancer problems.
Two of the awards are Community-Initiated Research Collaboration (CIRC) Awards. In a Pilot Award, a team (Mary Gould of Marin Breast Cancer Watch and Margaret Wrensch, Ph.D., of the University of California, San Francisco), will explore methods to collect information about adolescent years from older women, with a long-term goal of identifying factors in adolescence that might lead to breast cancer later in life. In a CIRC Full Research Award, Stephanie Roberts, M.D., of Lyon-Martin Women's Health Services and Suzanne Dibble, D.N.Sc., of the University of California, San Francisco, are working together to explore a commonly believed but unproven hypothesis that lesbians have higher frequencies of some known breast cancer risk factors, leading to a higher risk of breast cancer in this population.
An IDEA grant was awarded to Lisa Shames, Ph.D., M.P.H., of the University of Southern California, to explore the role of exercise in breast cancer recurrence. Several studies have suggested that exercise may reduce the risk of breast cancer, but whether it can also help in preventing recurrences of breast cancer has not yet been established.
It is strongly believed that life-long exposure to hormones contributes to the development of breast cancer, but individual differences in hormone levels and the risk associated with these are not understood. New hypotheses have been generated by the finding in earlier CBCRP-funded research that variations in genes involved in the production of estrogen may explain individual variations. This has led to a new study by Heather Feigelson, Ph.D., M.P.H., of the University of Southern California, exploring variations in two genes and their association with circulating blood levels of estrogen, as well as known risk factors for breast cancer. Understanding the biological basis for epidemiologic findings opens the door to risk identification, prevention and treatment tailored to individuals. These and other risks factors are also being explored in a hypothesis-generating study by Deirdre Hill, Ph.D., of the University of Southern California who will be receiving postdoctoral training in breast cancer research.
